The oral cavity serves two essential roles in the pathogenesis of HIV-1 infection. First, the oral mucosae, particularly tonsils, may provide a target of primary HIV-1 transmission from mother to infant through exposure to vaginal fluids at birth and to breast milk after birth and during passive oral sex among men. Second, tonsils may serve a less well-appreciated but no less critical role as the inductive sites for mucosal and systemic immune responses that can provide protection against HIV-1 transmission at both local and distant sites, particularly the cervicovaginal mucosae. In this defensive role, the oropharynx offers a unique window to characterize the efficiency of mucosal immune responses and confers an accessible and acceptable route for mucosal immunization. Thus, we propose to characterize responses to nasal immunization with a viral vaccine at local and distant mucosal sites (oropharynx and vagina), and in the systemic circulation. We propose that by understanding the inductive requirements and the anatomic distribution of these humeral and cellular responses, we will provide a clinical and immunologic basis for the development of effective mucosal vaccination against primary HIV-1 infection. Our concept is to provide protection at the mucosa, before infection is established, with a systemic component for added security. We will employ an RNA virus vaccine model (mucosal live attenuated influenzavirus) to advance the viability of such an approach as appropriate HIV-1 vaccine antigens become available (e.g., stable immunogenic oligomeric gp120/gp41; DNA-protein or-vector vaccines). Hypotheses: 1) Qrophayngeal immunization induces functional antiviral immune responses at local and distal mucosal sites and in blood; 2) Mucosal immunization elicits both humeral responses in the mucosa and CTL responses in the systemic compartment; and 3) Tonsils serve as the primary inductive sites for oropharyngeal immunization, and their absence will compromise local, vaginal, and systemic responses.